Primary myelofibrosis (PMF) is a type of chronic myeloproliferative neoplasm. Currently, research on the pathogenesis of myelofibrosis (MF) has been intensifying, and the treatments have been gradually improved. The current status of research on the diagnosis of PMF, risk stratification, benefits and potential toxicities of JAK kinase inhibitor therapy, and combination therapy are reviewed at the 2014 European Hematology Association (EHA) annual meeting.
1. Diagnosis of PMF
MF is a clonal proliferative stem cell disorder characterized by excessive secretion of pro-fibroblastic cytokines causing bone marrow fibrous tissue proliferation, extramedullary hematopoiesis and conversion to acute leukemia, including PMF, MF secondary to primary thrombocythemia (PET-MF) and MF secondary to true erythroblastosis (PPV-MF) .The typical clinical manifestations of PMF include significant enlargement of the spleen The main pathological changes on bone marrow biopsy are MF, as well as non-uniform and consistent fibrous tissue (reticulin); X-ray examinations show varying degrees of osteosclerosis, manifested by increased bone density with speckled translucent areas; the patient’s life expectancy is significantly shortened. To confirm the diagnosis of PMF, other diseases causing MF need to be excluded, such as chronic granulocytic leukemia, hairy cell leukemia, non-Hodgkin’s lymphoma, infections (tuberculosis, Leishmania protozoa), radiation, systemic sclerosis, and systemic lupus erythematosus. Although there are unclassified myeloproliferative neoplasms (MPN-U), there is insufficient information to make recommendations for the therapeutic management of MPN-U, and controversy exists regarding the diagnosis of early fibrosis or pre-MF. If reactive MF due to other diseases has been ruled out, relevant diagnostic information, such as JAK2V617F and CLAR mutations, should be used to classify MPN whenever possible and diagnose PMF based on a combination of clinical manifestations, bone marrow morphology, cytogenetics and molecular genetics evidence (Figure 1). Accurate diagnosis can guide the treatment of PMF and determine the prognosis.
2. Risk stratification of PMF
Factors affecting the prognosis of PMF include age, white blood cell count, hemoglobin content, peripheral blood naïve cell ratio, systemic symptoms, karyotype and specific gene mutations. Commonly used MF prognostic score systems include the International Prognostic Staging System (IPSS), Dynamic IPSS (DIPSS) and DIPSS plus . Compared to IPSS and DIPSS, DIPSSplus incorporates karyotype analysis and can more accurately distinguish between high- and low-risk patients. Karyotypes suggesting poor prognosis include +8, -7/7q-, inv(17q), inv(3), 12p-, 11q23 rearrangements, and complex karyotypes. Revisions to the above scoring system may include results for ASXL1, EZH2, IDH1/2, and SRSF2 (recent studies suggest that these mutations may indicate a poor prognosis and a high likelihood of conversion to acute leukemia), or a combined test for CLAR and ASXL1. However, screening for these mutations is not currently included in the routine screening and prognostic scoring system.
Causes of increased hemoglobin, in addition to true erythrocytosis, include chronic hypoxia, pulmonary disease, respiratory insufficiency, altitude sickness, congenital cyanotic heart disease, congenital oxygen transport disorders, hyperaffinity hemoglobinemia, defective erythrocyte metabolism (low 2,3-DPG) methemoglobinemia, heavy smoking (carboxyhemoglobinemia), renal tumors, cystic/polycystic kidney disease, renal transplantation, renal tissue hypoxia (e.g., renal artery stenosis), cerebellar hemangioma, hepatocellular carcinoma, androgen abuse, Cushing’s syndrome, primary aldosteronism, pheochromocytoma (rare), Barth syndrome; causes of thrombocytosis, in addition to primary thrombocytosis, are seen in iron deficiency anemia, blood loss (acute or chronic), splenectomy, post-surgery, sepsis, septicemia, meningitis, the abscesses of diverticula, etc., chronic inflammatory diseases (e.g., vasculitis), inflammatory bowel disease, connective tissue diseases, rheumatoid arthritis, and malignancies; myelofibrosis is also seen in malignant hematologic diseases (e.g., chronic myeloid leukemia), acute myelofibrosis (AML-M7), myelodysplastic syndrome, myeloma, hairy cell leukemia, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, systemic mastocytosis, metastatic carcinoma, infections (e.g., tuberculosis, leishmaniasis), drugs/toxins (e.g., benzene, thorium contrast), radiation, bone diseases (e.g., Paget’s disease), osteoporosis, hyperparathyroidism, hypoparathyroidism, systemic lupus erythematosus, and gray platelet syndrome.
3. Treatment of PMF
The most common cause of death in patients with MF is conversion to acute granulocytic leukemia (about 20% ). However, more patients die from other events related to MF, such as disease progression of non-leukemic lesions, severe systemic symptoms, cachexia, portal hypertension, and thrombosis or cardiovascular events. Currently, the main treatments for PMF include allogeneic hematopoietic stem cell transplantation, oral hydroxyurea to reduce leukocyte load, splenectomy or radiation therapy to the splenic area, transfusion of red blood cells and/or subcutaneous injection of erythropoietin, oral androgens and immunomodulators to improve anemia, and JAK kinase inhibitors targeting the JAK2V617F mutation.
(1) Clinical efficacy of JAK kinase inhibitors
① ruxolitinib
ruxolitinib was the first approved JAK kinase inhibitor, and its associated phase III clinical trial, the COMFORT trial, included MF patients with intermediate-risk 2 or high-risk IPSS stage, spleen at least 5 cm below the rib cage, and platelet count >100×109/L. The study not only confirmed the effect of ruxolitinib on spleen reduction, but also confirmed its efficacy in improving patients’ systemic symptoms and life expectancy. Its difference in improving patients’ systemic symptoms and quality of life was statistically significant, improving patient survival and reducing the risk of death by approximately 50%. Data from the COMFORTII study have previously shown that some MF patients treated with ruxolitinib had a variable reduction in JAK2V617F mutant allele load. The COMFORT study was the first to report a correlation between spleen enlargement and prognosis, with increasing spleen volume suggesting a poor prognosis and a 9% increased risk of death for every 50 ml increase in spleen volume. data from the COMFORT study showed that the most common side effects of ruxolitinib were The most common toxic side effects of ruxolitinib were anemia and thrombocytopenia. Hemoglobin levels reached their lowest point (approximately 10% decrease) at week 12 and stabilized at approximately 10 g/L below baseline by week 24, and platelets decreased by approximately 40% before reaching a stable state. However, treatment discontinuation due to severe anemia or thrombocytopenia was rare (<1% in all trial groups), and anemia and thrombocytopenia could be improved by reducing the dose of ruxolitinib. In the COMFORT study, the incidence of grade 3/4 non-hematologic adverse reactions was low, but infections were relatively common.
② Other JAK kinase inhibitors
a. fedratinib (SAR302503)
The recently completed phase D clinical trial of fedratinib (JAKARTA-2) showed some therapeutic efficacy of this agent in MF. A subsequent phase III study (JAKARTA) in a human group of patients who were intolerant or ineffective to ruxolitinib showed therapeutic effects of fedratinib in the interim, but the trial was stopped due to the occurrence of Wernicke’s encephalopathy in a higher number of cases.
b. pacritinib (SB1518)
pacritinib is an inhibitor of JAK2 and FLT3, and in early clinical trials it caused a lower degree of bone marrow depression but no severe anemia requiring transfusion. A phase III clinical trial (PERSIST-1) of oral pacritinib for the treatment of MF with low platelets and symptomatic splenomegaly (including PET-MF, PPV-MF and PMF) is underway
c. momelotinib (CYT387)
momelotinib is a JAK1/JAK2 inhibitor that has completed Phase I/II clinical trials. The main advantage is the reduction of transfusion dependence: 49 of 72 transfusion-dependent patients were discharged from transfusion and maintained for 12 weeks. phase III clinical trials of momelotinib are underway to further confirm its reliability in reducing transfusion dependence.
d. Other JAK kinase inhibitors
Other JAK kinase inhibitors include BMS-911543, NS-018, and INCB- 039110. The latter is a selective JAK1 inhibitor that reduced systemic symptoms in 75% of the human group and reduced spleen size in 14% of the subjects.
(2) Safety of JAK kinase inhibitors
Three safety issues regarding JAK kinase inhibitors have received much attention recently, including the risk of withdrawal syndrome, neurological toxicity, and infection. Early reports showed a significant and poorly prognostic inflammatory syndrome after ruxolitinib discontinuation, and no persistent similar adverse reactions were observed during the subsequent 3-year follow-up, suggesting that such reactions may be severe withdrawal inflammatory syndrome due to discontinuation of ruxolitinib, and that spleen size should be closely monitored if during ruxolitinib treatment If the spleen continues to grow during ruxolitinib treatment, there is a risk that symptoms associated with MF may return to baseline levels or even continue to progress after discontinuation of the drug. Therefore, when interruption of ruxolitinib treatment is considered, the dose should be gradually reduced or combined with corticosteroid therapy.
Clinical trials of fedratinib and XL109 were recently discontinued due to the induction of symptoms similar to Wernicke’s encephalopathy by fedratinib and the development of neurotoxicity in XL109. Although ruxolitinib has few similar adverse effects, a critical review of this class of compounds is still needed, and it is necessary to clarify whether JAK/STAT inhibitors affect thiamin metabolism or affect other JAK/STAT-dependent neural pathways.
In the COMFORT study, MF patients treated with ruxolitinib had a slightly higher probability of developing infections. Other related reports highlighting serious infections in JAK kinase inhibitor-treated patients include cryptococcal pneumonia, bilateral toxoplasma retinitis, hepatitis B virus reactivation, and one case of progressive multifocal cerebral white matter encephalopathy. One case of Mycobacterium tuberculosis infection was reported in the COMFORT-II study; and recently, lymph node tuberculosis was reported in 2 of 20 patients with MF treated with ruxolitinib in areas with a high incidence of tuberculosis. Possible mechanisms of susceptibility to infection include inhibition of proliferation, activation, and migration of dendritic cells of mononuclear origin and significant inhibition of proliferation and differentiation of T cells after exposure to ruxolitinib. It is therefore necessary to elucidate whether the effects of JAK kinase inhibitors on the immune system are general or specific. Related studies are in progress.
(3) Non-JAK kinase inhibitors
① Interferon
Interferon has been reported to ameliorate molecular abnormalities and reduce bone marrow fibrous tissue ± had production in early MF.
② Everolimus
Everolimus, an mTOR inhibitor, showed complete remission of systemic symptoms and skin pruritus in 69% and 80% of subjects in a phase I /II clinical study of 30 patients, respectively. The overall efficacy rate was 60% (8 major remissions, 7 partial remissions, and 3 minor remissions) when using the European MF Working Group’s efficacy criteria and 23% (1 partial remission and 6 clinical improvement) when using the IWGMRT criteria.
(iii) Pabisterostat
Pabisterostat is a pan deacetylase inhibitor and one patient achieved near complete remission after 16 months of treatment with this inhibitor.
④Pomalidumide
pomalidumide is an immunomodulatory agent. Pomalidumide was found to be very effective in improving anemia in a phase II clinical trial. However, in phase III clinical trials (RESUME), pomalidumide did not significantly improve transfusion dependence compared to the current “most effective treatment options” such as androgens, interferon, erythropoietin, and placebo, although it was effective in improving thrombocytopenia.
⑤ Hedgehogsignaling
Studies have shown abnormal hedgehog signaling pathways in hematologic malignancies. Hedgehog signaling and abnormalities in TGF-β1, mTOR and p53 were found in a mouse model of MF. The combination of JAK2 and Hedgehog inhibitors has recently been reported to improve the efficacy in mouse models. erismodegib (LDE225) and ruxolitinib combination therapy for PMF is in clinical trials.
(6) Lysyl oxidase-related agents
Lysyl oxidase (LOX) and lysyl oxidase-like (LOXL) catalyze the cross-linking of collagen and elastin and are aberrantly expressed in PMF patients. The use of an AB-0023 monoclonal antibody against LOXL2 was found to be therapeutic in rodent tumor models. simtuzumab (GS-6624), a humanized AB-0023, is safe and well tolerated in patients with liver disease and is currently in phase II trials for lung and liver fibrosis.
(7) imetelstat (GRN163L)
imetelstat is a telomerase inhibitor. Increased telomerase activity has been found in patients with MF. Nine of 22 patients with MF treated with imetelstat were effective, and four patients had reversal of MF and correction of abnormal megakaryocyte morphology. However, severe myelosuppression occurred, and more data are expected to support this.
(4) Combination therapy of PMF
The use of JAK kinase inhibitors in combination with conventional or experimental drugs is important in treating MF and improving the prognosis of MF patients. However, there is a huge challenge to assess the effect of these experimental therapies: to determine the overall survival or leukemia-free survival, a large patient population with long-term observation is required. The response rate of spleen volume (i.e., the percentage of spleen reduction) is now the standard endpoint or primary endpoint for determining the efficacy of PMF, but there is still a need to find new observational indicators, such as allelic load, CD34-cell count, MF grading, and other genetic signatures, to facilitate rapid determination of efficacy by changes in these indirect indicators when selecting novel agents or combination therapies.
①panobinostat in combination with ruxolitinib
The combination of panobinostat and ruxolitinib has been well tolerated and effective in the treatment of MF, and the combination has been shown to reduce spleen size and improve systemic symptoms associated with MF even at lower doses than those seen with monotherapy.
② ruxolitinib in combination with pegylated interferon
ruxolitinib in combination with pegylated interferon achieved rapid molecular remission of MF and was well tolerated.
(iii) JAK kinase inhibitor combined with allogeneic hematopoietic stem cell transplantation
In patients with MF who are likely to undergo allogeneic HSCT but have a significantly enlarged spleen and severe systemic symptoms, the use of JAK kinase inhibitors may rapidly shrink the spleen and improve the patient’s general condition to ensure transplantation. Two trials are currently underway, including the results of the JAK-ALLO study in France, which showed that the use of ruxolitinib prior to allogeneic HSCT may have unpredictable and serious toxicities: tumor lysis syndrome (3 cases) and cardiogenic shock (3 cases); these adverse effects should be carefully considered in other prospective clinical trials and in clinical practice.
4. Problems and outlook
The depth of research into the pathogenesis of PMF and the development of new treatments in recent years, as well as the continued benefit of patients from new regimens, are indeed encouraging. However, the long-term safety and efficacy of these new regimens must be evaluated. The development of JAK kinase inhibitors and combination therapy regimens will bring hope to more patients with PMF.